Abstract Plausible biological mechanisms remain elusive to explain the association between daily fluctuations in ambient air pollution and increased mortality rates. Epidemiological studies consistently identify aging and cardiopulmonary illness to be risk factors. Mechanistic studies in this proposal focus on interactions between age-dependent changes in the neurohumoral regulation of the heart and acute exacerbations in cardiopulmonary dysfunction induced by particulate matter (PM) exposures. Specifically, we will investigate the role atrial natriuretic peptide (ANP) and nitric oxide (NO) signaling pathways play in protecting the heart during acute exposures to PM. Central Hypothesis: Acute instability in cardiac function during PM exposure is exacerbated by the age-dependent loss of two cardioprotective mechanisms involving atrial natriuretic peptide and nitric oxide signaling pathways. These two signals converge to stimulate particulate and soluble guanylyl cyclase pathways, which routinely improve cardiopulmonary function and reduce cardiac stress. Specific Aim 1 tests whether age- dependent susceptibility to PM-induced cardiopulmonary dysfunction evolves from adverse modifications in natriuretic peptide regulation. Here, we test the hypothesis that PM uniquely challenges the pulmonary vasculature and right ventricular function. The protection afforded by natriuretic peptides wanes with age leaving the pulmonary vasculature and right ventricle susceptible PM exposure leading to dysfunctional changes. Specific Aim 2 tests whether age-dependent susceptibility to PM-induced cardiopulmonary dysfunction evolves from increased reactive oxygen species (ROS) derived from nitric oxide synthase (NOS)-uncoupling in isolated cardiac myocytes and cardiopulmonary endothelial cells. Here, a unique mechanism involving NOS3 activity being diverted to ROS formation is increased with age and induced acutely by PM exposure. Specific Aim 3 investigates whether acute exposures to ambient urban Baltimore air pollution alter cardiac function and lung inflammatory responses in senescent mice. In this final aim, exposure studies will evaluate the effects of "real-world" exposures to PM while assessing altered blood pressure regulation and in-vivo hemodynamic variables. Heart and lung biomarkers of air pollutant exposure will also be assessed to evaluate guanylyl cyclase signaling pathways. We believe this research plan uniquely examines plausible biological mechanisms to better understand the mortality risk which threatens susceptible elderly populations during episodes of poor air quality.